CA2744189C - Tgr5 modulators and methods of use thereof - Google Patents
Tgr5 modulators and methods of use thereof Download PDFInfo
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- CA2744189C CA2744189C CA2744189A CA2744189A CA2744189C CA 2744189 C CA2744189 C CA 2744189C CA 2744189 A CA2744189 A CA 2744189A CA 2744189 A CA2744189 A CA 2744189A CA 2744189 C CA2744189 C CA 2744189C
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- compound
- hydrogen
- tgr5
- ih3e
- hydroxy
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP08169462.2 | 2008-11-19 | ||
| EP08169462 | 2008-11-19 | ||
| PCT/US2009/065188 WO2010059853A1 (en) | 2008-11-19 | 2009-11-19 | Tgr5 modulators and method of use thereof |
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| CA2744189A1 CA2744189A1 (en) | 2010-05-27 |
| CA2744189C true CA2744189C (en) | 2016-10-11 |
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| USRE48286E1 (en) | 2001-03-12 | 2020-10-27 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for FXR |
| US10987362B2 (en) | 2004-03-12 | 2021-04-27 | Intercept Pharmaceuticals, Inc. | Treatment of fibrosis using FXR ligands |
| PT1734970E (pt) | 2004-03-12 | 2015-03-11 | Intercept Pharmaceuticals Inc | Tratamento de fibrose utilizando ligandos de rfx |
| ITMI20050912A1 (it) | 2005-05-19 | 2006-11-20 | Erregierre Spa | Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici |
| CN101679476B (zh) | 2007-01-19 | 2014-05-07 | 英特塞普特医药品公司 | 23取代的胆汁酸作为tgr5调节剂及其使用方法 |
| CN105037476B (zh) | 2008-07-30 | 2018-06-12 | 英特塞普特医药品公司 | Tgr5调节剂及其使用方法 |
| SG10201400162QA (en) * | 2008-11-19 | 2014-05-29 | Intercept Pharmaceuticals Inc | Tgr5 modulators and methods of use thereof |
| EP2364161B1 (en) * | 2008-11-26 | 2020-03-11 | Satiogen Pharmaceuticals, Inc. | Compositions containing satiogens and methods of use |
| CN102316872B (zh) | 2008-11-26 | 2016-12-21 | 萨蒂奥根制药公司 | 治疗肥胖症和糖尿病的胆汁酸再循环抑制剂 |
| ES2552657T3 (es) | 2010-05-26 | 2015-12-01 | Satiogen Pharmaceuticals, Inc. | Inhibidores del reciclado de ácidos biliares y saciógenos para el tratamiento de diabetes, obesidad, y afecciones gastrointestinales inflamatorias |
| DK2771003T3 (en) | 2011-10-28 | 2017-07-17 | Lumena Pharmaceuticals Llc | Bile acid recycling inhibitors for the treatment of pediatric cholestatic liver disease |
| JP6217939B2 (ja) | 2011-10-28 | 2017-10-25 | ルメナ ファーマシューティカルズ エルエルシー | 高胆汁血症および胆汁うっ滞性肝疾患の処置のための胆汁酸再利用阻害剤 |
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| SG10201607230SA (en) | 2012-06-19 | 2016-10-28 | Intercept Pharmaceuticals Inc | Preparation, Uses And Solid Forms Of Obeticholic Acid |
| WO2014059008A1 (en) | 2012-10-09 | 2014-04-17 | The Procter & Gamble Company | Method of identifying or evaluating beneficial actives and compositions containing the same |
| JP6189962B2 (ja) | 2012-10-09 | 2017-08-30 | ザ プロクター アンド ギャンブル カンパニー | 相乗作用する美容成分の組み合わせを特定する方法 |
| CN105408343B (zh) * | 2013-06-06 | 2018-08-03 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | 胆汁酸-碱性氨基酸缀合物及其用途 |
| US20160151486A1 (en) * | 2013-06-13 | 2016-06-02 | Fast Foward Pharmaceuticals B.V. | CD40 Signalling Inhibitor and a Further Compound, Wherein the Further Compound is a Bile Acid, a Bile Acid Derivative, an TGR5-Receptor Agonist, an FXR Agonist or a Combination Thereof, for the Treatment of Chronic Inflammation, and the Prevention of Gastrointestinal Cancer or Fibrosis |
| WO2015075557A2 (en) | 2013-11-22 | 2015-05-28 | Mina Alpha Limited | C/ebp alpha compositions and methods of use |
| SI3626725T1 (sl) * | 2014-05-29 | 2023-04-28 | Bar Pharmaceuticals S.R.L. | Derivati holana za uporabo pri zdravljenju in/ali preprečevanju bolezni, posredovanih s FXR in TGR5/GPBAR1 |
| US20180236064A1 (en) * | 2014-10-03 | 2018-08-23 | Mayo Foundation For Medical Education And Research | Targeting tgr5 to treat disease |
| KR20170094184A (ko) * | 2014-11-06 | 2017-08-17 | 이난타 파마슈티칼스, 인코포레이티드 | Fxr/tgr5 작용제로서의 담즙산 유사체 및 이의 이용 방법 |
| KR102527821B1 (ko) | 2014-11-19 | 2023-05-02 | 엔제트피 유케이 리미티드 | 스테로이드 FXR 조절인자를 제조하기 위한 중간체로서의 6α-알킬-6,7-다이온 스테로이드 |
| CA2968309A1 (en) | 2014-11-19 | 2016-05-26 | NZP UK Limited | 6-alkyl-7-hydroxy-4-en-3-one steroids as intermediates for the production of steroidal fxr modulators |
| MX375864B (es) | 2014-11-19 | 2025-03-07 | Nzp Uk Ltd | Esteroides de 5.beta-6-alquil-7-hidroxi-3-ona como intermedios para la produccion de moduladores esteroideos del receptor x farnesoide (fxr) |
| TWI686401B (zh) | 2014-11-19 | 2020-03-01 | 英商Ｎｚｐ英國有限公司 | 化合物（三） |
| CN105985396A (zh) * | 2015-02-16 | 2016-10-05 | 苏州泽璟生物制药有限公司 | 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 |
| CN111116699B (zh) * | 2015-04-28 | 2023-02-28 | 江苏豪森药业集团有限公司 | 胆酸衍生物及其制备方法和医药用途 |
| ES2873088T3 (es) * | 2015-06-19 | 2021-11-03 | Intercept Pharmaceuticals Inc | Moduladores de TGR5 y métodos para su uso |
| PT3310801T (pt) * | 2015-06-24 | 2021-06-18 | Intercept Pharmaceuticals Inc | Moduladores de tgr5 e métodos de utilização dos mesmos |
| CA2999302A1 (en) * | 2015-09-24 | 2017-03-30 | Intercept Pharmaceuticals, Inc. | Methods and intermediates for the preparation bile acid derivatives |
| AU2016335765B2 (en) | 2015-10-07 | 2022-01-06 | Intercept Pharmaceuticals, Inc. | Farnesoid X receptor modulators |
| CN109467585A (zh) * | 2016-03-11 | 2019-03-15 | 深圳市塔吉瑞生物医药有限公司 | 用于预防或治疗fxr-介导疾病的胆烷酸化合物 |
| CN109071452A (zh) | 2016-04-13 | 2018-12-21 | 英特塞普特医药品公司 | 治疗癌症的方法 |
| GB201608777D0 (en) | 2016-05-18 | 2016-06-29 | Dextra Lab Ltd | Compounds |
| CN115236166A (zh) | 2016-05-29 | 2022-10-25 | 深圳市绘云生物科技有限公司 | 肝病相关生物标志物和其使用方法 |
| US10654834B2 (en) * | 2016-07-01 | 2020-05-19 | Venenum Biodesign, LLC | Non-systemic TGR5 agonists |
| WO2018222701A1 (en) * | 2017-05-30 | 2018-12-06 | Intercept Pharmaceuticals, Inc. | Treatment of renal diseases with a bile acid derivative |
| CN109021056B (zh) * | 2017-06-09 | 2021-03-09 | 博瑞生物医药（苏州）股份有限公司 | 法尼酯x受体激动剂 |
| CA3070837A1 (en) | 2017-07-24 | 2019-01-31 | Intercept Pharmaceuticals, Inc. | Isotopically labeled bile acid derivatives |
| CA3075205A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
| GB201812382D0 (en) | 2018-07-30 | 2018-09-12 | Nzp Uk Ltd | Compounds |
| EP3920937A4 (en) * | 2019-02-04 | 2022-11-02 | Intercept Pharmaceuticals, Inc. | TREATMENT AND PREVENTION OF INFLAMATORY BOWEL DISEASES WITH A BILE ACID DERIVATIVE |
| CN116925168A (zh) * | 2019-08-23 | 2023-10-24 | 深圳云合医药科技合伙企业(有限合伙) | 胆汁酸衍生物及其组合物和应用 |
| IL291985A (en) | 2019-10-07 | 2022-06-01 | Kallyope Inc | Gpr119 agonists |
| PH12022552277A1 (en) | 2020-02-28 | 2024-03-04 | Kallyope Inc | Gpr40 agonists |
| WO2021236617A1 (en) | 2020-05-19 | 2021-11-25 | Kallyope, Inc. | Ampk activators |
| CA3183575A1 (en) | 2020-06-26 | 2021-12-30 | Iyassu Sebhat | Ampk activators |
| KR102693566B1 (ko) * | 2020-07-03 | 2024-08-08 | 주식회사 큐라클 | 지방간 질환의 예방 또는 치료를 위한 약학적 조성물 |
| CN113774142A (zh) * | 2021-10-11 | 2021-12-10 | 北京化工大学 | Tgr5在制备治疗肠癌药物及诊断性试剂盒中的应用 |
Family Cites Families (51)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0101554B1 (en) | 1982-07-29 | 1986-10-15 | Lehner A.G. | New derivatives of biliary acids, process for the production thereof and pharmaceutical compositions containing the same |
| IT1206112B (it) | 1983-04-29 | 1989-04-14 | Lehner Ag | Nuovi derivati di acidi biliari, procedimento per la loro preparazione e relative composizioni farmaceutiche. |
| IT1212835B (it) | 1983-08-18 | 1989-11-30 | Lehner Ag | Derivati di acidi biliari, procedimento per la loro preparazione e relative composizioni farmaceutiche. |
| US4892868A (en) * | 1984-08-17 | 1990-01-09 | Gipharmex, S.P.A. | Derivatives of biliary acids, process for the production thereof and corresponding pharmaceutical compositions |
| IT1196377B (it) * | 1984-12-21 | 1988-11-16 | Lehner Ag | Derivati di acidi biliari,procedimento per la loro preparazione e relative composizioni farmaceutiche |
| IT1223313B (it) | 1987-10-20 | 1990-09-19 | Gipharmex Spa | Derivati di acidi biliari loro preparazione e composizioni farmaceutiche che li contengono |
| US5175320A (en) | 1989-04-17 | 1992-12-29 | Giuliani S.P.A. | Fluorinated bile acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them |
| IT1229570B (it) | 1989-04-17 | 1991-09-04 | Giuliani Spa | Derivati fluorurati di acidi biliari, loro preparazione e composizioni farmaceutiche che li contengono. |
| DE69018592T2 (de) | 1989-12-13 | 1995-10-05 | Mitsubishi Chem Corp | Pyrazolylacrylsäure-Derivate, verwendbar als systemische Fungiziden in Pflanzen- und Materialschutz. |
| WO1997028149A1 (en) | 1996-02-02 | 1997-08-07 | Merck & Co., Inc. | Method for raising hdl cholesterol levels |
| GB9604242D0 (en) | 1996-02-28 | 1996-05-01 | Glaxo Wellcome Inc | Chemical compounds |
| GB9606805D0 (en) | 1996-03-30 | 1996-06-05 | Glaxo Wellcome Inc | Medicaments |
| US5689791A (en) | 1996-07-01 | 1997-11-18 | Xerox Corporation | Electrically conductive fibers |
| TR199900056T2 (xx) | 1996-07-12 | 1999-04-21 | Smithkline Beecham P.L.C. | Leptin direncinin yeni tedavisi. |
| US6008237A (en) | 1997-12-19 | 1999-12-28 | Merck & Co., Inc. | Arylthiazolidinedione derivatives |
| CA2318731C (en) | 1998-01-29 | 2012-05-29 | Tularik Inc. | Ppar-gamma modulators |
| AU1229000A (en) | 1998-10-23 | 2000-05-15 | Glaxo Group Limited | Assays for ligands for nuclear receptors |
| ES2326850T3 (es) | 1998-12-23 | 2009-10-20 | Glaxo Group Limited | Ensayos para ligandos de receptores nucleares. |
| US6465258B1 (en) | 1999-01-07 | 2002-10-15 | Tularik, Inc. | FXR receptor-mediated modulation cholesterol metabolism |
| US20020132223A1 (en) | 1999-03-26 | 2002-09-19 | City Of Hope | Methods for modulating activity of the FXR nuclear receptor |
| EP1473042B1 (en) | 1999-03-26 | 2006-06-21 | City of Hope | Screening for FXR receptor modulators |
| DE60029029T2 (de) | 1999-03-26 | 2007-06-14 | City Of Hope, Duarte | Screenen nach FXR-Rezeptormodulatoren |
| AU768806B2 (en) | 1999-06-11 | 2004-01-08 | Allergan, Inc. | Methods for modulating FXR receptor activity |
| US6906057B1 (en) | 1999-06-11 | 2005-06-14 | Allergan, Inc. | Methods for modulating FXR receptor activity |
| US6559188B1 (en) | 1999-09-17 | 2003-05-06 | Novartis Ag | Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes |
| EP1284728A4 (en) | 1999-10-22 | 2004-05-19 | Merck & Co Inc | MEDICINES FOR TREATING ADDICTIC ADDICTION |
| AU2001246905A1 (en) | 2000-04-12 | 2001-10-23 | Takeda Chemical Industries Ltd. | Novel g protein-coupled receptor protein and dna thereof |
| US6627636B2 (en) | 2000-06-15 | 2003-09-30 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
| WO2002020463A2 (en) | 2000-09-05 | 2002-03-14 | Tularik Inc. | Fxr modulators |
| US20020119958A1 (en) | 2001-02-13 | 2002-08-29 | Shinichiro Tojo | Therapeutic agent for hyperlipidemia |
| USRE48286E1 (en) | 2001-03-12 | 2020-10-27 | Intercept Pharmaceuticals, Inc. | Steroids as agonists for FXR |
| EP1378749A4 (en) | 2001-04-12 | 2005-05-11 | Takeda Pharmaceutical | SCREENING METHOD |
| WO2003015777A1 (en) | 2001-08-13 | 2003-02-27 | Lion Bioscience Ag | Nr1h4 nuclear receptor binding compounds |
| US20070010562A1 (en) | 2001-08-13 | 2007-01-11 | Ulrike Bauer | Nr1h4 nuclear receptor binding compounds |
| ATE381542T1 (de) | 2001-08-13 | 2008-01-15 | Phenex Pharmaceuticals Ag | Nr1h4-kern-rezeptor-bindende verbindungen |
| US20030144360A1 (en) | 2001-11-19 | 2003-07-31 | Allergan Sales, Inc. | Composition and method for modulating BAR/FXR receptor activity |
| US20050107475A1 (en) | 2002-03-21 | 2005-05-19 | Jones Stacey A. | Methods of using farnesoid x receptor (frx) agonists |
| EP1494533A2 (en) | 2002-04-12 | 2005-01-12 | The University of Chicago | Farnesoid x-activated receptor agonists |
| US6987121B2 (en) | 2002-04-25 | 2006-01-17 | Smithkline Beecham Corporation | Compositions and methods for hepatoprotection and treatment of cholestasis |
| AU2003244312B2 (en) | 2002-06-19 | 2008-07-03 | Availvs Corporation | Artificial stone wall material |
| ITMI20021532A1 (it) | 2002-07-12 | 2004-01-12 | Roberto Pellicciari | Composti chimici |
| EP1562915A1 (en) | 2002-11-22 | 2005-08-17 | SmithKline Beecham Corporation | Farnesoid x receptor agonists |
| EP1591120A4 (en) | 2003-01-28 | 2009-06-10 | Takeda Chemical Industries Ltd | RECEPTOR AGONISTS |
| WO2005032549A1 (en) | 2003-09-26 | 2005-04-14 | Smithkline Beecham Corporation | Compositions and methods for treatment of fibrosis |
| EP1568706A1 (en) | 2004-02-26 | 2005-08-31 | Intercept Pharmaceuticals, Inc. | Novel steroid agonist for FXR |
| PT1734970E (pt) | 2004-03-12 | 2015-03-11 | Intercept Pharmaceuticals Inc | Tratamento de fibrose utilizando ligandos de rfx |
| ITMI20050912A1 (it) | 2005-05-19 | 2006-11-20 | Erregierre Spa | Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici |
| JP5222846B2 (ja) | 2006-06-27 | 2013-06-26 | インターセプト ファーマシューティカルズ， インコーポレイテッド | Ｆｘｒ媒介疾患または状態の予防または治療のためのｆｘｒリガンドとしての胆汁酸誘導体 |
| EP1947108A1 (en) | 2007-01-19 | 2008-07-23 | Intercept Pharmaceuticals, Inc. | TGR5 modulators and methods of use thereof |
| CN101679476B (zh) * | 2007-01-19 | 2014-05-07 | 英特塞普特医药品公司 | 23取代的胆汁酸作为tgr5调节剂及其使用方法 |
| SG10201400162QA (en) * | 2008-11-19 | 2014-05-29 | Intercept Pharmaceuticals Inc | Tgr5 modulators and methods of use thereof |
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